EP1372742A2 - Grain de brachytherapie imageable polymere - Google Patents

Grain de brachytherapie imageable polymere

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Publication number
EP1372742A2
EP1372742A2 EP01273840A EP01273840A EP1372742A2 EP 1372742 A2 EP1372742 A2 EP 1372742A2 EP 01273840 A EP01273840 A EP 01273840A EP 01273840 A EP01273840 A EP 01273840A EP 1372742 A2 EP1372742 A2 EP 1372742A2
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EP
European Patent Office
Prior art keywords
seed
brachytherapy
seeds
brachytherapy seed
implantation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP01273840A
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German (de)
English (en)
Inventor
Edward J. Kaplan
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Microspherix LLC
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Microspherix LLC
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Filing date
Publication date
Priority claimed from US09/861,196 external-priority patent/US6514193B2/en
Application filed by Microspherix LLC filed Critical Microspherix LLC
Publication of EP1372742A2 publication Critical patent/EP1372742A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61NELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00Radiation therapy
    • A61N5/10X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
    • A61N5/1001X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy using radiation sources introduced into or applied onto the body; brachytherapy
    • A61N5/1027Interstitial radiation therapy
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0038Radiosensitizing, i.e. administration of pharmaceutical agents that enhance the effect of radiotherapy
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6957Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a device or a kit, e.g. stents or microdevices
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00Preparations for testing in vivo
    • A61K49/04X-ray contrast preparations
    • A61K49/0409Physical forms of mixtures of two different X-ray contrast-enhancing agents, containing at least one X-ray contrast-enhancing agent which is not a halogenated organic compound
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/12Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
    • A61K51/1282Devices used in vivo and carrying the radioactive therapeutic or diagnostic agent, therapeutic or in vivo diagnostic kits, stents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61NELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00Radiation therapy
    • A61N5/10X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
    • A61N5/1001X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy using radiation sources introduced into or applied onto the body; brachytherapy
    • A61N2005/1019Sources therefor
    • A61N2005/1023Means for creating a row of seeds, e.g. spacers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61NELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00Radiation therapy
    • A61N5/10X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
    • A61N5/1001X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy using radiation sources introduced into or applied onto the body; brachytherapy
    • A61N2005/1019Sources therefor
    • A61N2005/1024Seeds

Definitions

  • This application relates to imagable implantable brachytherapy devices, and methods of use thereof.
  • Radioactive seed therapy is an established technique for treating various medical conditions, most notably prostate cancer.
  • brachytherapy is an established technique for treating various medical conditions, most notably prostate cancer.
  • about 50-150 small seeds containing a radioisotope that emits a relatively short-acting type of radiation are surgically implanted in the diseased tissue. Because the seeds are localized near the diseased tissue, the radiation they emit is thereby concentrated on the cancerous cells and not on distantly located healthy tissue.
  • brachytherapy is advantageous over conventional external beam radiation.
  • a number of devices have been employed to implant radioactive seeds into tissues. See, e.g., U.S. Patent Nos.
  • an implantation device having a specialized needle is inserted through the skin between the rectum and scrotum into the prostate to deliver radioactive seeds to the prostate.
  • the needle can be repositioned or a new needle used for other sites in the prostate where seeds are to be implanted.
  • 20-40 needles are used to deliver between about 50-150 seeds per prostate.
  • a rectal ultrasound probe is used to track the position of the needles. Once the end of a given needle is positioned in a desired location, a seed is forced down the bore of the needle so that it becomes lodged at that location.
  • the needles are removed from the patient. Over the ensuing several months the radiation emitted from the seeds kills the cancerous cells. Surgical removal of the seeds is usually not necessary because the type of radioisotope generally used decays over the several month period so that very little radiation is emitted from the seeds after this time.
  • Currently marketed radioactive seeds take the form of a capsule encapsulating a radioisotope.
  • the capsule of these seeds is made of a biocompatible substance such as titanium or stainless steel, and is tightly sealed to prevent leaching of the radioisotope.
  • the capsule is sized to fit down the bore of one of the needles used in the implantation device. Since most such needles are about 18 gauge, the capsule typically has a diameter of about 0.8 mm and a length of about 4.5 mm.
  • the two radioisotopes most commonly used in prostate brachytherapy seeds are iodine (1-125) and palladium (Pd-103). Both emit low energy irradiation and have half-life characteristics ideal for treating tumors. For example, 1-125 seeds decay at a rate of 50% every 60 days, so that at typical starting doses their radioactivity is almost exhausted after ten months. Pd-103 seeds decay even more quickly, losing half their energy every 17 days so that they are nearly inert after only 3 months.
  • Radioactive brachytherapy seeds may also contain other components.
  • seeds may contain a radiopaque marker.
  • Markers are typically made of high atomic number (i.e., "high Z") elements or alloys or mixtures containing such elements. Examples of these include platinum, iridium, rhenium, gold, tantalum, lead, bismuth alloys, indium alloys, solder or other alloys with low melting points, tungsten, and silver.
  • Many radiopaque markers are currently being marketed. Examples include platinum/iridium markers (Draximage, Inc.
  • radiopaque markers include polymers impregnated with various substances (see, e.g., U.S. Patent No. 6,077,880).
  • U.S. Patent No. 3,351,049 to Lawrence discloses the use of a low-energy X-ray- emitting interstitial implant as a brachytherapy source.
  • U.S. Patent No. 4,323,055 to Kubiatowicz; 4,702,228 to Russell; 4,891,165 to Suthanthiran; 5,405,309 to Garden; 5,713,828 to Coniglione; 5,997,463 to Cutrer; 6,066,083 to Slater; and 6,074,337 to Tucker disclose technologies relating to brachytherapy devices. All of these devices are permanent, however. It is an object of the present invention to provide biodegradable seeds.
  • a brachytherapy seed that includes a drug or other therapeutically active substance that can be delivered to a subject upon implantation into the subject through the bore of a brachytherapy implantation needle has been developed. Because the brachytherapy seeds can be sized and shaped to fit through the bore of a brachytherapy implantation needle, they are suitable for use with brachytherapy seed implantation instruments such as an • implant needle, a Henschke, Scott, or Mick applicator, or a similar device such as a Royal Marsden gold grain gun.
  • a drug or other therapeutically active substance or diagnostic can be included in the seed in addition to, or as an alternative to, a radioisotope.
  • the rate of release in the implantation site can be controlled by controlling the rate of degradation and/or release at the implantation site.
  • the seeds also contain a radioopaque material or other means for external imaging.
  • the seeds can be precisely implanted in many different target tissues without the need for invasive surgery.
  • the therapeutically active substance included within a seed can be delivered in a controlled fashion over a relatively long period of time (e.g., weeks, months, or longer periods).
  • the brachytherapy seeds offer other advantages. Among these, for example, compared to conventional systemic administration (e.g., oral or intravenous delivery) of therapeutically active substances, the brachytherapy seeds can provide higher and more consistent concentrations of a therapeutically active substance to a target tissue.
  • a target tissue lacks an intact vascular supply (e.g., a target tissue whose blood flow may be compromised) or is otherwise sequestered from the blood supply (e.g., via the blood-brain barrier of the central nervous system).
  • a radioisotope e.g., those having only the therapeutically active substance and biodegradable component
  • FIG. 1 is a schematic side view of a cyhndrically shaped brachytherapy seed.
  • FIG. 2 is a schematic side view of a hollow tube-shaped brachytherapy seed.
  • FIGs. 3A-3G are schematic side views of several versions of brachytherapy seeds including a radiopaque marker.
  • FIG. 4A is a schematic view of a brachytherapy seed having a sealed container housing a radioisotope partially coated by a therapeutically active component and a biocompatible component.
  • FIG. 4B is a cross-sectional view of a brachytherapy seed having a sealed container housing a radioisotope completely coated by a therapeutically active component and a biocompatible component.
  • FIG. 5A is a schematic view of a flaccid chain of several brachytherapy seeds conjoined with several spacer elements.
  • FIG. 5B is a schematic view of a rigid cha in of several brachytherapy seeds conjoined with several spacer elements.
  • a brachytherapy seed has been developed for implantation into a subject which includes a biocompatible component, a therapeutically active component that includes a non-radioactive drug, and in a preferred embodiment, a radiopaque marker.
  • the biocompatible component is physically associated with a therapeutically active component and in contact with the marker.
  • the brachytherapy seed includes a non- metal biocompatible component, a therapeutically active component comprising a radioisotope, and a radiopaque or other diagnostic marker, the biocompatible component being (a) physically associated with a therapeutically active component and (b) in contact with the diagnostic marker, wherein the brachytherapy seed has a size and shape suitable for passing through the bore of a needle typically having an interior diameter of less than about 2.7 millimeters (10 gauge).
  • Brachytherapy seeds typically have a size and shape suitable for passing through the bore of a needle having an interior diameter of less than about 2.7 millimeters (10 gauge), less than about 1.4 millimeters (15 gauge), less than about 0.84 millimeters (18 gauge), or less than about 0.56 millimeters (24 gauge).
  • the seed is shaped into a cylinder having a diameter of between about 0.5 to 3 millimeters and a length 4 to 10 millimeters, e.g., one wherein the diameter is about 0.8 millimeters and the length is about 4.5 millimeters.
  • the biocompatible component is biodegradable.
  • suitable materials include polymers such as polyhydroxy acids (polylactic acid, poly gly colic-lactic acid), poly anhydrides (poly(bis(p-carboxyphenoxy) propane anhydride, poly(bis(p-carboxy) methane anhydride), copolymer of poly- carboxyphenoxypropane and sebacic acid); polyorthoesters; polyhydroxyalkanoates (polyhydroxybutyric acid); and poly (isobutylcyanoacrylate).
  • polymers such as polyhydroxy acids (polylactic acid, poly gly colic-lactic acid), poly anhydrides (poly(bis(p-carboxyphenoxy) propane anhydride, poly(bis(p-carboxy) methane anhydride), copolymer of poly- carboxyphenoxypropane and sebacic acid); polyorthoesters; polyhydroxyalkanoates (polyhydroxybutyric acid); and poly (isobutylcyanoacrylate).
  • open cell polylactic acid examples include open cell polylactic acid; co-polymers of a fatty acid dimer and sebacic acid; poly(carboxyphenoxy) hexane; poly-l,4-phenylene dipropionic acid; polyisophthalic acid; polydodecanedioic acid; or other polymers described below.
  • Biomaterials Engineering and Devices Human Applications : Fundamentals and Vascular and Carrier Applications, Donald L. Wise et al. (eds), Humana Press, 2000; Biomaterials Science : An Introduction to Materials in Medicine. Buddy D. Ratner et al. (eds.), Academic Press, 1997; and Biomaterials and Bioengineering Handbook. Donald L. Wise, Marcel Dekker, 2000.
  • polymers can be obtained from sources such as Sigma Chemical Co., St. Louis, MO; Polysciences, Warrenton, PA; Aldrich, Milwaukee, WI; Fluka, Ronkonkoma, NY; and BioRad, Richmond, CA, or can be synthesized from monomers obtained from these or other suppliers using standard techniques. Formation of Polymeric Seeds
  • polylactic acid seeds can be fabricated using methods including solvent evaporation, hot-melt microencapsulation and spray drying.
  • Poly anhydrides made of bis-carboxyphenoxypropane and sebacic acid or poly(fumaric-co- sebacic) can be prepared by hot-melt microencapsulation.
  • Polystyrene seeds can be prepared by solvent evaporation.
  • Hydrogel seeds can be prepared by dripping a polymer solution, such as alginate, chitosan, alginate/polyethylenimine (PEI) and carboxymethyl cellulose (CMC), from a reservoir though microdroplet forming device into a stirred ionic bath, as disclosed in PCT WO 93/21906.
  • One or more diagnostic, therapeutic or prophylactic compounds can be incorporated into the polymeric seeds either before or after formation.
  • Seeds with different sizes (1-1000 ⁇ m) and morphologies can be obtained by this method.
  • This method is useful for relatively stable polymers like polyesters and polystyrene.
  • labile polymers such as poly anhydrides, may degrade during the fabrication process due to the presence of water.
  • some of the following methods performed in completely anhydrous organic solvents are more useful.
  • Seeds can be formed from polymers such as polyesters and polyanhydrides using hot melt microencapsulation methods as described in Mathiowitz et al, Reactive Polymers, 6:275 (1987). In this method, the use of polymers with molecular weights between 3-75,000 Daltons is preferred.
  • the polymer first is melted and then mixed with the solid particles of a substance to be incorporated that have been sieved to less than 50 ⁇ m. The mixture is suspended in a non-miscible solvent (like silicon oil), and, with continuous stirring, heated to 5 °C above the melting point of the polymer. Once the emulsion is stabilized, it is cooled until the polymer particles solidify. The resulting seeds are washed by decantation with petroleum ether to give a free-flowing powder. Seeds with sizes between 1 and 1000 ⁇ m are obtained with this method.
  • a non-miscible solvent like silicon oil
  • This technique is primarily designed for polyanhydrides and is described, for example, in PCT WO 93/21906, published November 11, 1993.
  • the substance to be incorporated is dispersed or dissolved in a solution of the selected polymer in a volatile organic solvent like methylene chloride.
  • This mixture is suspended by stirring in an organic oil, such as silicon oil, to form an emulsion. Seeds that range between 1-300 ⁇ m can be obtained by this procedure.
  • Methods for forming seeds using spray drying techniques are well known in the art.
  • the polymer is dissolved in an organic solvent such as methylene chloride.
  • a known amount of a substance to be incorporated is suspended (insoluble agent) or co-dissolved (soluble agent) in the polymer solution.
  • the solution or the dispersion then is spray-dried. Seeds ranging between 1 and 10 ⁇ m are obtained.
  • This method is useful for preparing seeds for imaging of the intestinal tract. Using the method, in addition to metal compounds, diagnostic imaging agents such as gases can be incorporated into the seeds. Phase Inversion
  • Seeds can be formed from polymers using a phase inversion method wherein a polymer is dissolved in a good solvent, fine particles of a substance to be incorporated, such as a drug, are mixed or dissolved in the polymer solution, and the mixture is poured into a strong non-solvent for the polymer, to spontaneously produce, under favorable conditions, polymeric seeds, wherein the polymer is either coated on the particles or the particles are dispersed in the polymer.
  • the method can be used to produce micr op articles in a wide range of sizes, including, for example, about 100 nm to about 10 ⁇ m.
  • Exemplary polymers which can be used include polyvinylphenol and polylactic acid.
  • Substances which can be incorporated include, for example, imaging agents such as fluorescent dyes, or biologically active molecules such as proteins or nucleic acids.
  • Protein seeds can be formed by phase separation in a non- solvent followed by solvent removal as described in U.S. Patent No. 5,271,961 to Mathiowitz et al.
  • Proteins which can be used include prolamines such as zein. Additionally, mixtures of proteins or a mixture of proteins and a bioerodable material polymeric material such as a polylactide can be used.
  • a prolamine solution and a substance to be incorporated are contacted with a second liquid of limited miscibility with the proline solvent, and the mixture is agitated to form a dispersion. The prolamine solvent then is removed to produce stable prolamine seeds without crosslinking or heat denaturation.
  • Other prolamines which can be used include gliadin, hordein and kafirin. Low Temperature Casting of Seeds
  • Seeds made of gel-type polymers are produced through traditional ionic gelation techniques.
  • the polymer first is dissolved in an aqueous solution, mixed with a substance to be incorporated, and then extruded through a microdroplet forming device, which in some instances employs a flow of nitrogen gas to break off the droplet.
  • a slowly stirred ionic hardening bath is positioned below the extruding device to catch the forming microdroplets.
  • the seeds are left to incubate in the bath for twenty to thirty minutes in order to allow sufficient time for gelation to occur.
  • Particle size is controlled by using various size extruders or varying either the nitrogen gas or polymer solution flow rates.
  • Chitosan seeds can be prepared by dissolving the polymer in acidic solution and crosslinking it with tripolyphosphate.
  • Carboxymethyl cellulose (CMC) seeds can be prepared by dissolving the polymer in acid solution and precipitating the microsphere with lead ions.
  • Alginate/polyethylene imide (PEI) can be prepared in order to reduce the amount of carboxylic groups on the alginate microcapsule. The advantage of these systems is the ability to further modify their surface properties by the use of different chemistries. In the case of negatively charged polymers (e.g., alginate, CMC), positively charged ligands (e.g., pol lysine, polyethyleneimine) of different molecular weights can be ionically attached. Fluidized Bed
  • Particles, including seeds can be formed and/or coated using fluidized bed techniques.
  • One process is the Wurster air- suspension coating process for the coating of particles and seeds. The process consists of supporting the particles in a vertical column of heated air while the particles pass an atomizing nozzle that applies the coating material in the form of a spray. Enteric and film coating of seeds by this process typically requires approximately 30 minutes.
  • Suitable coating materials include, but are not limited to, cellulose acetate phthalate, ethylcellulose, hydroxypropyl methylcellylose, polyethylene glycol, and zein.
  • the Wurster apparatus provides controlled cyclic movement of the suspended particles by a rising stream of warm air, the humidity, temperature, and velocity of the air regulated.
  • An air- suspended or fluidized bed of particles has a random movement. If seeds move in and out of a coating zone in a random manner, the coating can be applies only at a slow rate.
  • the Wurster apparatus provides better drying and eventually a more uniform coating by imparting a controlled cyclic movement without or with less randomness.
  • a support grid at the bottom of the vertical column typically includes a course screen, e.g., 10 mesh, and a fine screen, e.g., 200 mesh. The fine screen offers considerably more resistance to the air flow than the coarse screen; thus, the greater amount of air flows through the coarse screen.
  • the air flowing through coarse screen lifts the seeds upward in the column. As the velocity of the air stream is reduced due to diffusion of the stream and resistance of the seeds, the upward movement of the seeds ceases. Then the seeds enter the region of a still lower velocity air stream above the fine screen, where they dry and gently settle. As the dried and partially coated seeds approach the grid, they are again introduced into the higher-velocity air stream the coarse screen and enter into another cycle.
  • the coating fluid is dispersed by atomization under pressure.
  • a compressed- air inlet is connected to the atomizing the solution or slurry of the coating material.
  • the seeds which are suspended above the coarse screen, have little contact with each other, so the coating fluid is readily distributed onto the surface of the seeds in the moving bed. As the cyclic movement of the seeds continues, the seeds are presented many times in many different positions to the atomized spray; therefore, a uniform coating is built up on the seeds. Coating is controlled by the weight of the coated seeds, formulation of the coating, temperature, time, and air velocity. Particle sizes can vary from about 50 ⁇ m to about 2 mm or greater.
  • Polymers can be used to form, or to coat, drug delivery devices such as seeds or seeds containing any of a wide range of therapeutic and diagnostic agents. Any of a wide range of materials can be incorporated into the seeds including organic compounds, inorganic compounds, proteins, polysaccharides, and nucleic acids, such as DNA, using standard techniques. Any of a wide range of therapeutic, diagnostic and prophylactic materials can be incorporated into the seeds, including organic compounds, inorganic compounds, proteins, polysaccharides, and nucleic acids, such as DNA, using standard techniques.
  • the non-radioactive drug can take the form of stimulating and growth factors; gene vectors; viral vectors; anti-angiogenesis agents; cytostatic, cytotoxic, and cytocidal agents; transforming agents; apoptosis-inducing agents; radiosensitizers; radioprotectants; hormones; enzymes; antibiotics; antiviral agents; mitogens; cytokines; anti-inflammatory agents; immunotoxins; antibodies; or antigens.
  • the non-radioactive therapeutic can be an anti-neoplastic agent such as paclitaxel, 5- fluorouracil, or cisplatin.
  • radiosensitizing agent such as 5- fluorouracil, etanidazole, tirapazamine, BUdR, or IudR.
  • radiosensitizing agent such as 5- fluorouracil, etanidazole, tirapazamine, BUdR, or IudR.
  • Many different therapeutically active substances have been associated with biocompatible materials for use in drug delivery systems apart from brachytherapy seeds. These include, for example, adriamycin (Moritera et al., Invest. Ophthal. Vis. Sci.
  • camptothecin Weingart et al., Int. J. Cancer
  • nerve growth factor (Camerata et al., Neurosurgery 30:313-19, 1992); retroviral vector producer cells to transfer a cytotoxic gene product (Beer et al., Adv. Drug Deliver. Rev. 27:59-66, 1997 ); taxol (Park et al., J. Controlled Rel. 52:179- 189, 1998; and Harper, E et al., Clin. Cancer Res., 5:4242-4248, 1999); tetanus toxoid (Alonso et al., Vaccine 12:299-306, 1994); tetracaine hydrochloride (Ramirez et al., J. Microencap.
  • cytokines e.g., Edelman E.R. et al., Biomaterials 12:619-26, 1991
  • cytotoxic agents e.g., Brem H. et al., J. Neurosurg. 80:283-90, 1994; Brem H. et al., J. Neurosurg. 80:283-90, 1994; Brem H. et al., Lancet 345:1008-12, 1995;Ewend M.G. et al., Cancer Res. 56:5217-23, 1996; Fung L.K. et al., Cancer Res. 58:672-85, 1998; Grossman S.
  • hormones e.g., Rosa G.D. et al., J. Control Release 69:283-95, 2000
  • immunosuppressants e.g., Sanchez A. et al., Drug Delivery 2:21-8, 1995
  • mitogens e.g., Ertl B. et al., J. Drug Target 8:173-84, 2000
  • neurotransmitters e.g., During M. J. et al., Ann Neurology 25:351- 6, 1989
  • radioprotectants e.g., Monig H. et al., Strahlenther Onkol. 166:235-41, 1990
  • radiosensitizers e.g., Williams J.A.
  • Diagnostic compounds can be magnetic (detectable by MRI), radioopaque (detectable by x-ray), fluorescent (detectable by fluorescent techniques) or ultrasound detectable. These materials are commerically available, as are the systems for detection and measurements.
  • Radiopaque marker 30 can be made of any substance that can be detected by conventional X-ray imaging techniques. See, e.g., Fundamentals of Diagnostic Radiology, 2d edition, William E. Brant and Clyde A. Helms (eds.), Lippincott, Williams and Wilkins, 1999; Physical Principles of Medical Imaging, 2d ed., Perry Jr. Sprawls, Medical Physic Publishing, 1995; Elements of Modern X-ray Physics, Jens Als-Nielsen and Des McMorrow, Wiley & Sons, 2001; X-ray and Neutron Reflectivity: Principles and Applications, J.
  • marker 30 Many such substances that can be used as marker 30 are known including, most notably, high atomic number (i.e., "high Z") elements or alloys or mixtures containing such elements. Examples of these include platinum, iridium, rhenium, gold, tantalum, bismuth alloys, indium alloys, solder or other alloys, tungsten and silver.
  • radiopaque markers that might be adapted include platinum/iridium markers from Draximage, Inc.; and International Brachytherapy; gold rods from Bebig GmbH; gold/copper alloy markers from North American Scientific, palladium rods from Syncor; tungsten markers from Best Industries; silver rods from Nycomed Amersham; silver spheres from International Isotopes Inc, and Urocor, and silver wire from Implant Sciences Corp.
  • Other radiopaque markers include polymers impregnated with various substances (see, e.g., U.S. Patent Nos. 6,077,880; 6,077,880; and 5,746,998).
  • Radiopaque polymers are described in European Patent Application 894, 503 filed May 8, 1997; European Patent Application 1,016,423 filed December 29, 1999; and published PCT application WO 9605872 filed August 21, 1995.
  • Those radiopaque polymers that are biodegradable are preferred in applications where it is desired to have the implant degrade over time in the implantation site.
  • radiopaque markers include platinum, iridium, rhenium, gold, tantalum, bismuth, indium, tungsten, silver, or a radiopaque polymer.
  • Suitable radioisotopes include 125 1 and 103 Pd. Sometimes combinations of agents may provide enhanced results.
  • a radiosensitizing agent such as 5- FU, etanidazole, tirapazamine, BUdR
  • IUdR a radiosensitizing agent
  • Various combinations of substances are known to be more effective when used in combination than when used alone. See, e.g, Brem et al., J. Neurosurg. 80:283-290, 1994; Ewend et al., Cancer Res. 56:5217- 5223, 1996; Cardinale, Radiation Oncol. Investig. 6:63-70, 1998; Yapp et al., Radiotherapy and Oncol.
  • the method of making a brachytherapy seed for implantation into a subject includes the steps of: (a) providing a non-metal biocompatible component and a therapeutically diagnostic or prophylactic (method to include here as "therepeutically active") active component, optimally further including an imaging agent; (b) physically associating the biocompatible component and the therapeutically active component to form a combination product; and (c) forming the combination product into a seed having a size and shape suitable for passing through the bore of a needle having an interior diameter of less than about 2.7 millimeters (10 gauge), less than about 1.4 millimeters (15 gauge), or less than about 0.84 millimeters (18 gauge), or less than about 0.56 millimeters (24 gauge).
  • FIG.l there is shown a brachytherapy seed 10 composed of a biocompatible component 12 associated with a therapeutically active component 14 (schematically shown as small circles or spheres).
  • the therapeutically active component 14 is present as a plurality of small particles dispersed throughout a matrix consisting of the biocompatible component 12.
  • the mixture of the components 12 and 14 is formed into the cylindrically shaped brachytherapy seed 10.
  • the brachytherapy seed 10 shown in FIG. 1 has a size and shape suitable for passing through the bore of a brachytherapy implantation needle.
  • the bore can be any size compatible with brachytherapy methods, in order to minimize damage to tissue, the bore preferably has an interior diameter of between about 0.01 and 10 mm (e.g., 0.009, 0.01, 0.02, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 4, 5, 6, 7, 8, 9, 10, or 11 mm).
  • 0.01 and 10 mm e.g., 0.009, 0.01, 0.02, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7,
  • seed 10 For use with 10 gauge or less brachytherapy implantation needles, seed 10 has a size and shape that can pass through a bore having a diameter of less than about 2.7 millimeters (i.e., the interior diameter of a standard 10 gauge brachytherapy implantation needle). For smaller needles such as 15 and 18 gauge needles, seed 10 has a size and shape that can pass through bores having an interior diameter of less than about 1.4 millimeters (e.g., 1.40, 1.39, 1.38, 1.37, 1.36, 1.35, or 1.34 mm) or less than about 0.84 millimeters (e.g., 0.86, 0.85, 0.84, 0.83, 0.82, 0.81, 0.80 mm), respectively.
  • 1.4 millimeters e.g., 1.40, 1.39, 1.38, 1.37, 1.36, 1.35, or 1.34 mm
  • 0.84 millimeters e.g., 0.86, 0.85, 0.84, 0.83, 0.82, 0.81, 0.80
  • seed 10 Although there is no lower limit as to how small any dimension of seed 10 can be, in many applications, those that are not able to pass through bores smaller than 0.3 mm are preferred. For example, in many applications where it is desirable for the implanted brachytherapy seeds to maintain their orientation in the tissue, the seed 10 should be large enough to stay lodged at the site of implantation in the desired orientation for a relatively long period, larger seeds are preferred. In some cases, the selection of materials for use in the seed 10 will affect its size. For instance, in versions of the seed 10 where the biocompatible component 12 is a stainless steel or titanium capsule, the walls of the capsule may need to be greater than a certain minimum size in order to maintain the structural integrity of the seed 10.
  • the seed 10 should also be large enough to carry a sufficient amount of the therapeutically active component 14 to be therapeutically active (i.e., a therapeutically effective amount or an amount that exerts a desired medically beneficial effect).
  • a sufficient amount of the therapeutically active component 14 to be therapeutically active i.e., a therapeutically effective amount or an amount that exerts a desired medically beneficial effect.
  • the diameter of seed 10 be just slightly less than the diameter of the bore of the needle (e.g., 0.5-5 % less).
  • brachytherapy seeds shaped into a cylinder (or rod) having a diameter of between about 0.8 to 3 millimeters and a length of between about 4 to 10 millimeters are preferred. Because many conventional brachytherapy seed applicators make use of brachytherapy implantation needles about 17 to 18 gauge in size, cylindrically shaped brachytherapy seeds having a diameter of between about 0.8 and 1.1 mm and a length greater than the diameter (e.g., 2-10 mm) are preferred for use with such applicators.
  • brachytherapy seed applicators are designed to accept conventional radioactive brachytherapy seeds that have a diameter of about 0.8 millimeters and a length of about 4.5 millimeters, brachytherapy seeds of similar size are especially preferred.
  • Brachytherapy seeds are not limited to those being cylindrical in shape (e.g., seed 10 shown in FIG. 1), but rather can be any shape suitable for passing through the bore of a needle.
  • seeds can be cuboid, spheroid, ovoid, ellipsoid, irregularly shaped, etc.
  • the ends of the seeds can be rounded, squared, tapered, conical, convex, concave, scalloped, angular, or otherwise-shaped.
  • the brachytherapy seeds can be solid as shown in FIG. 1, and have one or more cavities or pores (e.g., to increase the surface area of the seed exposed to the target tissue). As one example, as illustrated in FIG.
  • a brachytherapy seed 10 is shaped into a hollow tube 18 having a cylindrical cavity 20.
  • cylindrical cavity 20 is sized to accept and envelop a standard-sized brachytherapy seed (e.g., one having a diameter of about 0.8 mm and a length of about 4.5 mm).
  • the seed 10 can be placed over the standard-sized brachytherapy seed, and introduced into the bore of a needle (sized to accept the enveloped seed) for implantation into a target tissue.
  • the seed 10 shown in FIG. 2 can also be used alone without being placed over a standard-sized brachytherapy seed, e.g., to increase the surface area exposed in the site of implantation.
  • Hollow tube 18 can have any wall thickness or length suitable for wholly or partially enveloping a standard-sized brachytherapy seed and passing through the bore of a needle. Preferably it has a wall thickness between about 0.01 and 0.1 mm and a length of between about 1 to 4.5 mm .
  • biocompatible component 12 can be composed of any material suitable for implantation in a target tissue in an animal subject (e.g., a mammal such as a human patient) that can be associated with therapeutically active component 14 such that all or part of the therapeutically active component 14 will be delivered to the target tissue when the brachytherapy seed 10 is introduced into the implantation site, as discussed above.
  • an animal subject e.g., a mammal such as a human patient
  • the biocompatible component 12 be biodegradable (i.e., made of a substance other than titanium or stainless steel).
  • a biocompatible and biodegradable material made up of a chemical composition of a polymer known to degrade at a desired rate when placed under conditions similar to those encountered in the implantation site can be selected for use as component 12.
  • biodegradable components are described, e.g., in Biomaterials Engineering and Devices: Human Applications : Fundamentals and Vascular and Carrier Applications; Biomaterials Science : An Introduction to Materials in Medicine; and Biomaterials and Bioengineering Handbook, supra.
  • the duration of release of the therapeutically active component 14 from seed 10 can be varied from less than about an hour to more than about several months (e.g., 10 min., 30 min., 1 h., 2 h., 3 h., 6 h., 12 h., 1 day, 2 days, 3 days, 1 week, 2 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 1 year, 2 years, or 3 years).
  • Biocompatible component 12 is not limited to being biodegradable.
  • component 12 can also be made of a non- biodegradable material such as stainless steel or titanium.
  • biocompatible component 12 can be coated or otherwise associated with therapeutically active component 14, such that component 14 will be delivered to a target tissue into which seed 10 is implanted.
  • component 12 might take the form of a porous stainless steel or titanium cylinder having a plurality of pores through its outer surface, such pores being filled with or otherwise in communication with the component 14 such that the component 14 can diffuse from the seed 10 into the environment surrounding the seed 10 (e.g., a target tissue).
  • a test composition can be fashioned into a brachytherapy seed and implanted in a laboratory animal in a selected target tissue. The effects of the implanted compositions on the animal can then be monitored over a period of time.
  • the therapeutically active component 14 is a material that can (a) be implanted in a target tissue of an animal subject (e.g., a mammal such as a human patient) to exert an effect on the animal's physiology, and (b) be associated with the biocompatible component 12 in the brachytherapy seed 10.
  • a target tissue of an animal subject e.g., a mammal such as a human patient
  • Myriad different substances can be used as the therapeutically active component 14. See, e.g., Physician's Desk Reference, The Merck Index, and USP DI ® 2000 published by U.S.
  • the therapeutically active component 14 can include a small molecule drug (e.g., a non-peptide or non-nucleic acid- based molecule with a molecular weight generally less than 5 kDa) such as a chemical with known anti-cancer properties. It can also include a biologic such as a polypeptide (e.g., an antibody or a cytokine) or nucleic acid (e.g., an expression vector).
  • a small molecule drug e.g., a non-peptide or non-nucleic acid- based molecule with a molecular weight generally less than 5 kDa
  • a biologic such as a polypeptide (e.g., an antibody or a cytokine) or nucleic acid (e.g., an expression vector).
  • the therapeutically active substance 14 can include a anti-neoplastic drug such as paclitaxel (taxol), cisplatin, or 5-fluorouracil; or a hormone such as leuprolide.
  • the therapeutically active substance 14 can include a radio- sensitizing agent such as tirapazamine, BUdR, IUdR, or etanidazole.
  • the therapeutically active substance 14 may include a drug that is usually considered too toxic to treat a given condition if given systemically, e.g., tirapazamine or camptothecin.
  • the seed is coated with a non-radioactive biodegradable coating which degrades at a rate slower than that which allows the radioactivity to leach out, so that radioactivity is not released — i.e., the radioactivity has already fully decayed.
  • the biocompatible component 12 is associated with the therapeutically active component 14.
  • the phrase "associated with" means physically contacting.
  • the association of the biocompatible component 12 with the therapeutically active component 14 can take many forms.
  • the biocompatible component 12 and the therapeutically active component 14 can be combined into a mixture as shown in FIGs. 1 and 2. This mixture can have a uniform or non-uniform distribution of components 12 and 14.
  • the brachytherapy seed 10 shown in FIG. 1 is an example of a uniform mixture of components 12 and 14.
  • the brachytherapy seed 10 of this example can be made by simply mixing together the biocompatible component 12 and the therapeutically active component 14 to form a combination product and then forming the product into the desired size and shape, e.g., using a mold.
  • brachytherapy seeds shown in FIGs. 1 and 2 include mixtures of discrete particles dispersed through a matrix consisting of the therapeutically active component 14, in other versions of brachytherapy seed 10, components 12 and 14 are combined in a single particle or in a larger mass without discrete particles (e.g., a pellet the size and shape of brachytherapy seed 10).
  • biocompatible component 12 and therapeutically active component 14 can be dissolved into a liquid and then dried or cured to form seeds or a larger pellet made up of a homogeneous distribution of both components 12 and 14. (see, e.g., Ramirez et al., J. Microencapsulation 16:105, 1999).
  • the seeds are also made to include magnetic elements.
  • the seeds can then be molded or compressed together into the desired shape and sized of brachytherapy seed 10.
  • the larger pellet can likewise be sculpted, extruded, molded or compressed into the desired shape and size of brachytherapy seed 10.
  • the liquid mixture of components 12 and 14 can be poured into a mold defining the shape and size of brachytherapy seed 10, and then cured in the mold.
  • Brachytherapy seeds having components 12 and 14 combined in a single particle or in a larger mass (rather than discrete particles of each) are advantageous for delivering the therapeutically active component 14 into a target tissue over longer time periods.
  • components 12 and 14 are not necessarily homogeneously mixed in the seed 10. Rather they can be positioned in different areas of the seed 10.
  • components 12 and 14 can separately be fashioned into discrete sections, strips, coils, tubes, etc.
  • the discrete sections, strips, coils, tubes, etc. of the component 12 can then be combined (e.g., by molding together, adhering, structurally interlocking, etc.) with the discrete sections, strips, coils, tubes, etc. of the component 14 to form the seed 10.
  • the seed 10 shown in FIG. 2 can be modified by filling the cylindrical cavity 20 with a hydrogel, including a therapeutically active substance, and capping off the ends of the hollow tube 18.
  • the foregoing combination products i.e., at least one biocompatible component mixed with at least one therapeutically active component
  • a brachytherapy seed 10 includes a biocompatible component 12 associated with a therapeutically active component 14, and a radiopaque marker 30 attached to the biocompatible component 12 and/or the therapeutically active component 14.
  • Radiopaque marker 30 allows for the position of brachytherapy seed 10 to be determined using standard X-ray imaging techniques (e.g., fluoroscopy) after seed 10 has been implanted in a target tissue. Proper positioning of seed 10 and spacing of a plurality of brachytherapy seeds in a given target tissue is important for ensuring that the therapeutically active component 14 is delivered adequately to the site of the disease in the target tissue.
  • radiopaque marker 30 is attached to seed 10 via the biocompatible component 12 and/or the therapeutically active component 14.
  • the exact manner in which radiopaque marker 30 is attached to seed 10 can is not critical so long as (a) the seed 10 can be passed through the bore of a brachytherapy implantation needle and (b) the attachment allows the position of seed 10 to be readily detected by X-ray imaging.
  • FIGs. 3A-F A description of some different examples of how marker 30 can be associated with seed is presented in FIGs. 3A-F.
  • the radiopaque marker 30 in the form of a ribbon, filament, strip, thread, or wire is placed in the center and along the length of cylindrical seed 10.
  • the radiopaque marker 30 takes the form of two end caps placed at both ends of cylindrical seed 10.
  • the radiopaque marker 30 is a coil made of a radiopaque substance running through the length of cylindrical seed 10 as shown.
  • the radiopaque marker 30 takes the form of two beads or pellets placed at two locations along cylindrical seed 10.
  • the radiopaque marker 30 takes the form of two bands or rings placed at two locations along the outer surface of cylindrical seed 10.
  • the radiopaque marker 30 takes the form of a mesh formed into cylindrical shape.
  • the radiopaque marker 30 is dispersed throughout the seed in a stippled pattern.
  • a particularly preferred embodiment of a brachytherapy seed having a radiopaque marker is one in which the radiopaque markers is a polymer.
  • radiopaque polymers are combined with a biocompatible component and a therapeutically active component to form a brachytherapy seed that can be visualized by X-ray imaging.
  • the radiopaque polymer can serve as the biocompatible component.
  • seeds made of a radiopaque polymer are co-mingled with seeds containing a biocompatible component and seeds containing (e.g., encapsulating) a therapeutically active component (or seeds containing both a biocompatible component and a therapeutically active component).
  • the co-mingled seeds are then molded into a radiopaque brachytherapy seed.
  • the radiopaque polymer, the biocompatible component, and the therapeutically active component can be mixed together into a liquid, and the liquid can be cured to form a solid pellet that can be sculpted, molded, compressed, or otherwise made into the size and shape of a brachytherapy seed.
  • a brachytherapy seed 10 includes a biocompatible component 12 associated with a therapeutically active component 14, and a sealed container 40 housing a radioisotope 42.
  • Sealed container 40 is at least partially coated (e.g., partially coated in the version shown in FIG. 4A, and completely coated in the version shown in FIG. 4B) by the biocompatible component 12 and/or the therapeutically active component 14.
  • Sealed container 40 is similar in some respects to those employed in conventional radioactive brachytherapy seeds (e.g., those lacking a biocompatible component 12 associated with a therapeutically active component 14).
  • sealed container 40 is made of a non-biodegradable substance such as titanium or stainless steel. Further, radioisotope 42 is hermetically sealed within container 40.
  • sealed container 40 is not critical as long as it can be at least partially coated with component 12 and/or 14 to form a brachytherapy seed that can fit through the bore of a brachytherapy implantation needle. It can thus vary in shape from cylindrical (as shown in FIG. 4), cuboid, spheroid, ovoid, ellipsoid, irregularly shaped, etc. Of more importance is the size of sealed container 40. Because the brachytherapy seed 10 containing both the sealed container 40 and the biocompatible component 12 and/or therapeutically active component 14 must fit through the bore of a brachytherapy implantation needle, container 40 must be smaller than the overall size of seed 10. In the example shown in FIG.
  • sealed container 40 is a cylindrical cannister placed down the center of the length of the rod-shaped seed 10 in a coaxial fashion.
  • the sealed container will have a diameter less than 0.8 mm and a length less than 4.5 mm, and rather than having only a single sealed container 40 included within brachytherapy seed 10, there can be two or more such containers housing the radioisotope 42.
  • the therapeutically active agent 14 in seed 10 including the sealed container 40 can be any of those agents described above. Preferably, however, agent 14 is selected to provide an enhanced effect when used in combination with the radioisotope 42 to treat a particular diseased tissue, as discussed above.
  • Radioisotope 42 can be any substance that emits electromagnetic radiation (e.g., gamma-rays or X-rays), beta- particles or alpha-particles and is suitable for use in brachytherapy seed 10.
  • examples of such substances include those that decay principally by electron capture followed by X-ray emission such as palladium- 103 and iodine- 125; isotopes that decay by the emission of beta-particles such as gold-198, gold-199, yttrium-90, and phosphorus-32; isotopes that decay with the emission of both beta-particles and gamma-rays such as iridium- 192; and isotopes that decay with the emission of alpha-particles such as americium-241.
  • gadolinium- 157 e..g, for use in boron-neutron capture therapy, and californium-252, rhenium- 188, samarium-153, indium-Ill, ytterbium- 169, and holmium-166.
  • palladium- 103 and iodine- 125 are preferred as these have been the subject of much clinical investigation for the treatment of the disease.
  • the amount of radioactivity of radioisotope 42 can vary widely.
  • an exemplary amount to treat prostate cancer is respectively about 1.5 mCi and 0.33 mCi per seed if about 50-150 seeds are used at the time of implantation.
  • the radioactivity per seed can range from about 0.01 mCi to May 1, 2001 about 100 mCi.
  • radioisotope 42 can be mixed with and then configured into seeds, or it can be encapsulated by the biocompatible component to form seeds.
  • the radioactive seeds can be molded or otherwise sized and shaped into a brachytherapy seed suitable for implantation via a brachytherapy implantation device.
  • the biocompatible component is biodegradable such that the radioisotope contained by this component is gradually released from the seed.
  • the biocompatible component and radioisotope can be mixed together and configured as an amorphous pellet having the size and shape of a brachytherapy seed suitable for implantation via a brachytherapy implantation device. In another embodiment illustrated in FIGs.
  • a plurality of brachytherapy seeds 10 may be conjoined into a chain 50 using a plurality of spacers 52 to connect the plurality of seeds 10.
  • a spacer 52 is used to connect two adjacent seeds 10.
  • Spacer 52 can have any size suitable for use with brachytherapy seed 10. Where a plurality of spacers are used in one chain 50, the length of each spacer 52 can be the same or different from the other spacers 52. For many applications the length of spacer 52 will vary from between about 0.5 mm to about 50 mm.
  • Spacer 52 can be made of a biocompatible material that can be used to join two brachytherapy seeds. See, e.g., U.S. Patent No. 6,010,446.
  • the biocompatible material can be either biodegradable or non-biodegradable.
  • spacer 52 can be made of catgut or a like material. Spacers designed for use with conventional radioactive brachytherapy seeds can be used in chain 50. For example, Ethicon, Inc.
  • the spacer 52 may include a radiopaque substance (e.g., a high Z material or radiopaque polymer described above), so that spacer 52 serves both to facilitate locating an implanted brachytherapy seed by X-ray imaging as well as to physically join together (and/or control the distance between) two or more seeds.
  • a radiopaque substance e.g., a high Z material or radiopaque polymer described above
  • Spacer 52 can be connected to seed 10 by any means known.
  • spacer 52 can be connected to seed 10 by direct attachment such as by gluing, crimping, or melting.
  • Spacer 52 can be attached to any portion of the seed 10.
  • spacer 52 be attached to the ends of the seeds 10 that the ends would be adjacent to one another when the chain 50 is inserted into the barrel of a brachytherapy implantation needle.
  • Spacer 52 and seed 10 need not be physically attached to each other. Rather they can also be associated with each other by placing each with within the lumen of a tube.
  • the tube can be used to load a brachytherapy seed implantation device with a plurality of spacers 52 and seeds 10 in any sequence.
  • the brachytherapy seed implantation device can be loaded with one (or 2, 3, 4, 5, or more) spacer 52 being interposed between every two seeds 10.
  • the brachytherapy seed implantation device can be loaded with one (or 2, 3, 4, 5, or more) seed 10 being interposed between every two spacers 52.
  • the brachytherapy seeds are implanted into a target tissue within a subject (e.g., a human patient or a non-human animal) by adapting known methods for implanting conventional radioactive brachytherapy seeds into a tissue.
  • the brachytherapy seeds can be implanted using one or more implantation needles; Henschke, Scott, or Mick applicators; or a Royal Marsden gold grain gun (H. J. Hodt et al., British J. Radiology, pp. 419-421, 1952).
  • a number of suitable implantation devices are described in, e.g., U.S. Patent Nos. 2,269,963; 4,402,308; 5,860,909; and 6,007,474.
  • brachytherapy seeds into a target tissue using a brachytherapy implantation device so that a precise number of seeds can be implanted in precise locations within the target tissue.
  • an appropriate dosage can be delivered to the target tissue.
  • brachytherapy implantation devices allows the brachytherapy seeds to be implanted in any number of different desired locations and/or patterns in a tissue, this method is advantageous over methods where a drug or drug impregnated matrix is simply placed on the surface of a tissue or manually inserted into a surgically dissected tissue.

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Abstract

On a mis au point un grain de brachythérapie, qui contient un marqueur d'imagerie et/ou un agent thérapeutique, diagnostique ou prophylactique, tel qu'un médicament, dans un excipient polymère, pouvant être administré à un sujet par implantation dans le corps dudit sujet à travers le passage d'une aiguille d'implantation de brachythérapie. Dès lors que les grains de brachythérapie peuvent être dimensionnés et façonnés pour passer dans le passage d'une aiguille d'implantation de brachythérapie, ils sont appropriés pour être utilisés avec des instruments d'implantation de grains de brachythérapie. Un médicament ou une autre substance thérapeutiquement active ou de diagnostic peut être inclus dans le grain en plus ou en remplacement d'un radio-isotope. La vitesse de la libération sur le site d'implantation peut être régulée par régulation de la vitesse de dégradation et/ou de libération sur le site d'implantation. Dans le mode de réalisation préféré, ces grains contiennent également une substance radio-opaque ou un autre moyen d'imagerie externe. Comme les grains de brachythérapie radioactifs traditionnels, ces grains peuvent être implantés avec précision dans un grand nombre de tissus cibles différents, sans chirurgie invasive. En outre, tout comme le rayonnement émis par les grains de brachythérapie traditionnels, la substance thérapeutiquement active incluse dans un grain peut être administrée de façon régulée sur une période relativement longue (par exemple des semaines, des mois ou des périodes plus longues).
EP01273840A 2000-11-16 2001-11-16 Grain de brachytherapie imageable polymere Withdrawn EP1372742A2 (fr)

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US24912800P 2000-11-16 2000-11-16
US249128P 2000-11-16
US09/861,196 US6514193B2 (en) 2000-11-16 2001-05-18 Method of administering a therapeutically active substance
US861196 2001-05-18
US861326 2001-05-18
US09/861,326 US6746661B2 (en) 2000-11-16 2001-05-18 Brachytherapy seed
PCT/US2001/043517 WO2002068000A2 (fr) 2000-11-16 2001-11-16 Grain de brachytherapie imageable polymere

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AU2003267309A1 (en) 2000-11-16 2004-04-08 Microspherix Llc Flexible and/or elastic brachytherapy seed or strand
US8827884B2 (en) 2009-08-06 2014-09-09 Koninklijke Philips N.V. Oncology therapies employing radioactive seeds
CA3059534A1 (fr) 2017-05-11 2018-11-15 Alpha Tau Medical Ltd. Revetements polymeres pour dispositifs de brachytherapie
EP3773896A4 (fr) * 2018-04-02 2022-01-12 Alpha TAU Medical Ltd. Libération contrôlée de radionucléides
JP2024503995A (ja) 2020-12-16 2024-01-30 アルファ タウ メディカル リミテッド ベータ線治療を強化した拡散アルファ放射体放射線治療

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NZ511762A (en) * 1993-07-19 2003-09-26 Univ British Columbia Anti-angiogenic compositions and methods of use
US5716981A (en) * 1993-07-19 1998-02-10 Angiogenesis Technologies, Inc. Anti-angiogenic compositions and methods of use
US5626829A (en) * 1994-11-16 1997-05-06 Pgk, Enterprises, Inc. Method and apparatus for interstitial radiation of the prostate gland
US6503186B1 (en) * 1997-08-01 2003-01-07 North American Scientific, Inc. Radioactive seed with multiple markers and method for using same
AU1821200A (en) * 1998-12-03 2000-06-19 Scimed Life Systems, Inc. Stent having drug crystals thereon
US6132359A (en) * 1999-01-07 2000-10-17 Nycomed Amersham Plc Brachytherapy seeds
AR022404A1 (es) * 1999-01-25 2002-09-04 Photogen Inc Metodo y agentes para la terapia de radiacion mejorada
ATE339960T1 (de) * 1999-03-01 2006-10-15 Halogenetics Inc Verwendung von zusammensetzungen enthaltend cldc als strahlungssensibilisatoren in der behandlung von neoplastischen erkrankungen
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